This subproject will be devoted to genotyping a large number of new polymorphisms in part found by us, and in part found by external initiatives. We plan to genotype DNAs supplied by the world wide collection of cell lines being developed at CEPH in collaboration with us, with the aim of understanding the history of human evolution and the role of the classical evolutionary factors (mutation, natural selection, drift and migration) in determining human genetic variation. The genotyping method will be that developed in the course of this Program Project for finding and testing new genetic polymorphisms, DHPLC (Denaturing High Performance Liquid Chromatography). It will be perfected or replaced by other methods should a new one prove more valuable in terms of cost, given equal accuracy. In particular, we will analyze the variation of the whole mitochondrial DNA (excluding the D-loop, which has already been widely explored). At the time the new Program Project begins, we expect to have generated about 450 mostly new mtDNA SNPs. We also want to type, in the same way, a large number of Y chromosome mutants, which we plan to continue to provide, with the support of another grant, NIH GM55273, from an increasing variety of Y chromosome locations on the chromosome. A selected number of known X chromosome genes will be similarly studied in males. We have shown that Y mutants have a variation between populations almost three times larger than mtDNA mutants. We have given reasons that lead us to believe this finding is mostly due to the difference in matrimonial migration of males and females, as wives relocate at marriage more frequently than husbands do. We want to test this hypothesis further with the new data and independent methods. This should also allows us to test our findings on the relative variation between and within populations of autosomes, Y chromosome and mtDNA. X chromosomes should show another, predictable pattern. In all these situations we plan to use a variety of methods of statistical analysis, including new ones we have developed, based on the distribution of the number of mutants, and on their geography of mutants. We aim to reconstruct and date migrations during the expansion of modern humans in the last 100,000 years, and to understand more about the role of evolutionary factors, including mutation and selection.